Greetings, and welcome to the Cue Biopharma Fourth Quarter and Full Year 2022 Earnings Call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. Dan Passeri, Chief Executive Officer. Please go ahead..

Yes. Thank you, and good afternoon, everyone. As a reminder, this conference will be recorded and available on our website for the next 30 days. Also as a reminder, those listening in, just be aware of the webcast, you need to advance the slides as you are listening, and we'll notify you which slide we're on at a given time.

Joining me on today's call is Dr. Matteo Levisetti, our Chief Medical Officer; Dr. Ken Pienta, now in the role as a Clinical Advisory Cue; Dr. Anish Suri, our President and Chief Scientific Officer; and Kerri Millar, Chief Financial Officer. Also joining us briefly on today's call is Dr.

Sara Pai, Surgical Oncologist and Director of Translational Head and Neck Cancer Research at the Mass General Hospital. She is an investigator in our ongoing trial with CUE-101. We'll provide a brief perspective of clinical observations to date. In addition to Dr. Pienta, Dr.

Pai has also recently become a clinical adviser to Cue Biopharma helping to define our clinical strategies going forward. As shown here on Slide 2, this presentation and overview may contain some forward-looking statements, and any forward-looking statements made during this call represents the company's views as of today, March 21, 2023.

On the next slide, please. You'll see our agenda for today's call. Just want to please note that on this slide under the financial results, that's meant to read fourth quarter 2022, not third quarter. Apologies for that. We just noticed that before the call. Okay.

I'll begin by providing an overview and status update of our current corporate positioning, and we'll describe our competitive advantage, which we believe places us in a differentiated strategic position of strength and opportunity despite the present challenges of the capital markets.

We're also well positioned with capital into the second half of '24. And importantly, our platform has generated numerous programs at various stages of development, representing multiple partnering opportunities.

As a reminder, we recently entered into a strategic partnership with Ono Pharmaceuticals for the development of CUE-401, which is our bispecific regulatory T cell inducer in activator for potentially addressing a broad spectrum of autoimmune diseases.

Importantly, this transaction was structured to provide us with requisite capital through program funding, thereby subsidizing the ongoing research and development costs with CUE retaining a 50% co-development option for the U.S. market. So this was obviously a very balanced transaction for the company.

CUE-101's clinical data continues to support the clinical validation and the corresponding reduction of risk for the entire IL-2-based CUE-100 series and importantly, appears to provide us with defined options for potential registration paths.

Both CUE-101 and CUE-102 currently in clinical development address significant unmet medical need across multiple cancer indications.

Based on the clinical data generated to date, we believe we're now well positioned with our oncology portfolio to seek partnerships and transactions similarly structured to the Ono partnership to ensure we retain involvement in upside -- optimal upside potential while addressing capital access for building out our promising pipeline of potentially breakthrough therapeutics.

As seen in the next slide, it's Slide number 4. We believe our corporate positioning and competitive advantage are firmly established on solid foundational data and CUE-101 as an exemplary of the CUE-100 series represents a potential therapeutic breakthrough.

To-date, CUE-101 has demonstrated, as you see on this slide, monotherapy activity in late-stage cancer patients. What's important here is this is a single-agent activity in patients that basically are refractory to various chemotherapies but also checkpoint inhibitors.

To-date, we're observing significant increase, that is at least a doubling of the overall response combination with checkpoint inhibition compared with historic monotherapy with checkpoint inhibitors. Favorable tolerability. We've dosed greater than 70 patients to date with no evidence of vascular leak syndrome or cytokine release syndrome.

Antibody-based design gives us favorable cost of goods for manufacturability, and actually, the drug to-date has demonstrated astonishingly stable characteristics whereas stability has gone out to greater than 36 months, significant regulatory advantages. We have Fast Track designation and both mono as well as combination.

And importantly, the FDA authorized CUE-102 IND based on the safety data from CUE-101, basically viewing CUE-101 as an analog with no requirement for IND-enabling toxicology and approval to start the trial at a higher dose, saving significant time and cost. Matteo will elaborate upon these observations momentarily.

We view the cumulative data as supportive of our central premise, namely that the Immuno-STAT platform and more specifically, the IL-2-based CUE-100 series represents a therapeutic breakthrough by harnessing nature's specificity.

That's through targeting the T cell receptor or TCR enabling the targeted delivery of cytokines such as IL-2 to disease-relevant T cells.

We believe this approach enables the achievement of a therapeutic index for IL-2 and other cytokines by avoiding the deleterious side effects of nonselective indiscriminate activity, often seen with other modalities.

As a reminder, our platform modularity allows us also to deploy other modulatory co-stimulators beyond IL-2 based on the same principle.

I'm now going to turn the call over to Matteo and then he'll be followed by Ken and Sara to generally describe the emerging clinical observations from our ongoing CUE-101 and CUE-102 trials, and Anish will then provide a brief summary for our autoimmune programs, emphasizing the recent developments, including the CUE-401 partnership with Ono.

Matteo?.

Thanks, Dan.

The clinical data from the ongoing CUE-101 trial continues to demonstrate robust metrics of clinical benefit for heavily pretreated recurrent metastatic HPV positive head and neck squamous cell carcinoma patients treated with monotherapy and for newly diagnosed patients with recurrent metastatic HPV positive head and neck cancer treated in combination with pembrolizumab.

As shown on Slide 5, data from the ongoing clinical trials with CUE-101 as monotherapy and in combination with pembrolizumab have provided clinical proof-of-concept in derisking of our Immuno-STAT platform.

The latest data generated to date in 2023 continues to support prior observations and further enhances our confidence in CUE-101 as a potential therapeutic for patients battling HPV-positive head and neck squamous cell carcinoma.

As previously and consistently stated, we believe CUE-101's mechanism of action, as evidenced by the ongoing data generated to date, provides effective and tolerated dose levels, enabling selective expansion of targeted tumor-specific T cells directly in the patient's body.

Recurrent metastatic HPV positive head and neck cancer is a tough incurable disease. The data we have observed throughout the monotherapy trial bolsters our position and enhances our confidence that CUE-101 is in fact stimulating the targeted cancer-specific T cells within a subset of these patients, resulting in demonstrable antitumor effect.

Furthermore, and importantly, we continue to observe an evolving pattern of enhanced survival in the monotherapy trial. We believe this enhanced survival is due to the persistent expansion of tumor-specific T cells given CUE-101's mechanism of action.

As shown on Slide 6, CUE-101 demonstrates well-behaved pharmacokinetics with low inter-patient variability at the recommended Phase 2 dose of 4 milligrams per kilogram.

The exposure pattern is consistent throughout multiple cycles of treatment without any attenuation of PK parameters, supporting the premise that there is no evidence of clinically relevant immunogenicity.

Regarding its pharmacodynamic or PD profile, CUE-101 treatment also results in a consistently observed sustained increase in natural killer cells or NK cells a positive attribute associated with an antitumor response as NK cells are known to assist in tumor killing. Importantly, we observed only a modest and transient increase in regulatory T cells.

Regarding the intended PD effect, i.e., activation of targeted tumor-specific T cells, we have observed, as shown in the middle panel, robust expansion of tumor-specific E7 reactive T cells in their peripheral blood of patients as early as one week after administration of CUE-101, paired and post-treatment biopsies demonstrate an increase in tumor infiltrating T cells and associated tumor necrosis.

In addition to the favorable PK and PD just described in patients with advanced HPV-positive head and neck cancer are experiencing intriguing patterns of clinical benefit. Three examples are shown on Slide 7.

Patient A, experienced a durable partial response with an approximate 60% reduction in tumor burden evident at six weeks after two cycles of CUE-101. This response lasted close to one year.

This patient demonstrated a significant reduction in HPV cell-free DNA that coincided with the initiation of the partial response and the HPV cell-free DNA was undetectable for most of the time on treatment.

Patient B, who remains on treatment at the present time for approximately 1.5 years has had stable disease with tumor burden reduction of approximately 20% observed at week 48 and maintained to the present time at greater than 75 weeks. Notably, this patient has also had complete disappearance of HPV cell-free DNA in the blood since week six.

And the undetectable HPV cell-free DNA, which is an increasingly recognized biomarker of disease activity is suggestive of a pathologic complete response, i.e., a potential cure in this patient who we expect may have surgical resection of the lesion for histopathological analysis.

Patient C has experienced tumor reduction after a prolonged period on drug where no resist based objective response was initially observed by imaging.

In this patient treated with CUE-101 at 2 milligrams per kilogram, we can see that the first several months appear to demonstrate gradual tumor growth even beyond the 20% threshold used by RECIST criteria. However, based upon the overall clinical status, the patient continued treatment.

After approximately six months, the tumor began to shrink and the patient remained on therapy for greater than 18 months after starting treatment with CUE-101. This observation consistent with observations made by others, demonstrates that kinetics of T cell antitumor activity may manifest over a long period of time.

The next slide, Slide 8, conveys our ongoing survival swimmer plot for the 20 patients dosed the recommended Phase II dose of 4 milligrams per kilogram.

The swimmer plot for the 20 patients dosed at the RP2D of 4 mgs per kg demonstrates a trend of increased survival of approximately 12 months median overall survival compared to the historic reported survival of approximately eight months observed in patients treated in the second line in the KEYNOTE-040 trial of pembrolizumab.

As any experience oncologist understands the survival with third-line treatment is expected to be less as the disease has further developed and become more unstable.

Our evolving data continues to support the premise that treatment with CUE-101 stimulates the patient's immune system and results in what appears to be a meaningful increase in survival for patients with advanced recurrent metastatic HPV positive head and neck cancer.

This monotherapy data has encouraged our principal investigators and offers a potential path forward to a registrational trial. As shown on Slide 9, CUE-101 and checkpoint inhibition have complementary mechanisms of action and preclinical studies have demonstrated enhanced response and survival when both are given in combination.

In this aggressive HPV-positive mirroring tumor model shown in the right panel, the survival curves demonstrated survival of 90% for mice treated with combination of CUE-101 in anti-PD-1 compared to the 0% and 20% and end-of-study survival for anti-PD-1 and CUE-101 monotherapy, respectively.

The demonstration of monotherapy activity in patients bolsters our beliefs that we should have observed complementary mechanistic effects in combination with pembrolizumab. As a reminder, the data from patients treated in the CUE-101 monotherapy trial.

Clearly, this approach supports the 2101 increases the number of tumor-specific T cells in the patient's body.

In the combination study with pembrolizumab, it appears that these activated T cells have greater capacity to kill cancer cells when coupled with the inhibition of the PD-1 pathway, a major mechanism used by cancer cells to prevent immune-mediated killing. As reported at SITC in November of last year and as shown on the waterfall plot on Slide 10.

Four of the first 10 evaluable patients treated at the recommended Phase II combination dose of CUE-101 at 4 milligrams per kilogram plus pembrolizumab have experienced partial responses, i.e., at least two consecutive scans demonstrating a cumulative reduction of tumor burden of minus 30% or greater.

Notably, three of the four partial responses have been observed in tumors with low PD-L1 expression as evidenced by CPS scores of 20 or less.

-- as has been indicated by other studies, tumors that had CPS scores greater than 20 have been more responsive to PD-1 blockade and exhibit higher objective response rates compared to tumors with CPS scores less than 20.

The overall response rate of greater than 40% observed with CUE-101 in combination with pembrolizumab to date compares favorably to the historical objective response rate of 19% and observed with pembrolizumab monotherapy in the KEYNOTE-048 study.

The follow-up data on these first 10 patients as well as new emerging data on additional patients treated with combination therapy continues to strengthen, and we look forward to providing an update on the cumulative data at an upcoming oncology meeting.

Key observations in patients treated with CUE-101 monotherapy in the third line and beyond include as detailed on Slide 11 demonstration of single-agent antitumor efficacy evidenced by RECIST based partial response and durable stable disease in third line and beyond recurrent metastatic head and neck cancer patients and a median overall survival benefit emerging from survival follow-up in the RP2D cohort.

As previously announced, the robust data on CUE-101's activity in monotherapy and in combination with pembrolizumab enabled the granting of Fast Track designation for the treatment of patients in both the first and third line setting.

The cumulative data from these ongoing trials with CUE-101 have provided us with clear evidence of targeted expansion of HPV E7-specific T cells with antitumor activity as a single agent and as a complementary mechanism with checkpoint inhibition for what we believe will broaden patient reach and enhance efficacy of checkpoint blockade therapy.

As such, we believe CUE-101 as our first biologic therapeutic from our CUE-100 series represents a potential therapeutic breakthrough for patients, and we look forward to providing you with updated additional data at an upcoming oncology conference.

Furthermore, we believe the data from CUE-101 has provided a derisking and mechanistic validation for additional biologics from the CUE-100 series beginning with CUE-102 as shown on Slide 12.

Regarding our progress update pertaining to CUE-102, which targets Wilms Tumor 1, positive tumors in a trial that is enrolling patients with advanced colorectal, gastric, pancreatic and ovarian cancers. We anticipate completing the dose escalation portion of the trial by midyear -- the treatment has been well tolerated with no DLTs observed to date.

We plan to present preliminary data from the dose escalation portion of this trial at an upcoming oncology conference. As a reminder, CUE-102 and CUE-101 tiered 99% amino acid sequence identity.

This enabled us to significantly decrease the development time and cost of CUE-102 as we were not required by the FDA to repeat IND-enabling toxicology studies for CUE-102, and we were also able to initiate the Phase I dose escalation study at 1 milligram per kilogram a dose at which we observed clear signs of biologic activity with CUE-101.

As Slide 13 shows, we are conducting the CUE-102 dose escalation study in colon, gastric, pancreatic and ovarian cancers. This design offers us the ability to perform monotherapy expansion studies any or all of the indications being evaluated in the dose escalation phase of the trial.

This trial is actively accruing and will be open at 15 sites throughout the United States. We plan to present additional data at an upcoming oncology conference and look forward to presenting the corresponding data. I will now turn the call over to Ken.

Ken?.

Thanks, Matteo.

The evolving and maturing data from these programs is so extremely gratifying for me to see early on as an adviser to Cue, I recommend the potential promise of the platform for engineering biologics that could target cancer-specific T cells and could potentially deliver clinically meaningful levels of IL-2 to patients without the well-known toxicities associated with IL-2 that we all are aware of, such as vascular leak syndrome and cytokine release syndrome observed with Aldesleukin.

I subsequently took on the role of acting CMO, to establish the initial clinical trials that would affect the behavior and therapeutic activity.

And I'm so proud to have Shepherd 101 and 102 to those initial clinical trials and very pleased to have handed the CMO role over to you, Matteo, as you've taken on the role to bring these maturing and promising programs forward.

Now once again, in the role of clinical advisers of the company, I look forward to continuing to help develop the CUE-101, 102 and future assets for the benefits of patients.

At this time, I'd like to take this opportunity to introduce Sara Pai, MD PhD who has served as our lead investigator for the CUE-101 program and has now joined me as a clinical adviser to the company. Dr.

Pai is one of the world's foremost experts not only in HPV-driven head and neck cancer, but all head and neck cancer and has deep expertise as a surgeon, scientist, taking care of patients with this disease as well as running a lab studying this disease as well as the development of clinical trials for testing agents in the treatment of cancer.

Sara, welcome..

Thank you, Ken. Well, it's exciting for me personally to help designed the original CUE-101 studies and to take part as an investigator on the trials.

It is important to emphasize that recurrent and/or metastatic HPV-associated head and neck cancer patients need new and promising therapies that have antitumor activity while also maintaining a good quality of life without the debilitating side effects of cancer treatment. What we have consistently observed with CUE-101 is activity as a monotherapy.

And furthermore, what appears to be synergistic activity in combination with KEYTRUDA even in those patients with a low PD-L1 biomarker score and these patients are often the most difficult to treat with immunotherapy. Therefore, CUE-101 is certainly hitting the mark by addressing this unmet clinical need.

Importantly, we have observed that CUE-101 is well tolerated at clinically active doses without many of the side effects associated with IL-2 when given systemically.

This attribute of CUE-101 is key since it creates a therapeutic index for IL-2, which historically has been a significant challenge and has limited the assessment of the full potential of this important cytokine for effective cancer immunotherapy.

To have some cancer patients on an immunotherapy agent for over a year with readily manageable side effects underscores the potential importance of CUE-101 or Immuno-STATs. This observation is highly relevant in the setting of an increasingly aging cancer patient population in which the median age is now 66.

I'm really looking forward to seeing the continued results of the trials. I will now hand the call back to Ken..

Thanks, Sara. And again, I want to thank you for your thoughtful offer to be available for a brief comment today and giving us your thoughts We really appreciate your participation and benefit from your advice device and guidance throughout this process.

And we continue to want to do that as we march forward to help these patients afflicted with this off of disease. We'll talk again soon. I'll now turn the call over to Anish who will discuss some recent developments in the autoimmune applications of the CUE platform along with the collaboration with Ono Pharmaceuticals for the development of CUE-401.

Anish?.

Thanks, Ken, and welcome to all joining this call. Let me begin by providing a perspective on the significant opportunities for resetting immune balance or functional tolerance within the broad spectrum of autoimmune diseases with our platform assets.

As shown here on Slide 14, we have developed an overarching strategy for addressing autoimmune and inflammatory disorders by focusing on three key approaches. The first approach is the selective induction and expansion of regulatory T cells, which are the natural guardians for controlling pathogenic inflammatory immune responses.

To that end, we have developed a unique bispecific biologic composed of an IL-2 variant and a variant of TGF-beta termed CUE-401 that has the potential to convert pathogenic T cells into regulatory T cells as well as expand the natural recurring regulatory T cells.

We recently announced our collaboration with Ono Pharmaceuticals that supports the development of CUE-401 through defined milestones. The second approach is a selective dampening and control of autoreactive T cells via our Immuno-STAT platform. This approach applies to those diseases with strong HLA association and known dominant driver autoantigens.

We have previously shared the proof-of-concept data for this approach in type 1 diabetes, we have selective inhibition of insulin reactive T cells.

And the third approach is the generation of bispecific molecules that incorporate the nonclassical HLA-G molecule, which has been implicated in activation of tolerogenic dendritic cells expansion of regulatory T cells and suppression of autoreactive T cells.

Incidentally, HLA-G is also recognized as an important checkpoint for cancer immunotherapy, where in tumors up-regulated HLA-G to escape immune detection.

For the remainder of this section, I will focus and highlight the significant differentiation and competitive position of CUE-401 in the induction of regulatory T cells, representing a significant potential value driver.

As shown in the next slide, CUE-401 is a highly differentiated approach from all other IL-2 mutein teams being pursued for expansion of regulatory T cells.

CUE-401 builds upon a wealth of knowledge gained within the immunology community over the past two decades, describing the fact that IL-2 and TGF-beta signals can convert peripheral CD4-positive T cells into regulatory T cells also known as induced Tregs or iTregs.

And in contrast to all other IL-2 mutein approaches that simply focus on the preexisting small fraction of natural Tregs or Tregs, CUE-401 generates new populations of induced Tregs and can also expand the pre-existing natural Tregs.

Importantly, and as we have demonstrated, CUE-401 can convert pathogenic autoreactive T cells into regulatory T cells, hence providing a very attractive opportunity to reset immune tolerance. This significant differentiation is highlighted in the table shown on the bottom of the slide comparing CUE-401 to other CD25 biased IL-2 mutein approach.

An example of CUE-401's activity is shown on the next slide, Slide 16. In this in vitro assays, CD4 positive T cells from patients suffering from inflammatory bowel disease or rheumatoid arthritis were treated with CUE-401 and then followed for the induction of FOXP3 as shown on the y-axis of the graph.

FOXP3 is the master transcription factor expressed by regulatory T cells and is obligatory for the lineage differentiation of T cells into regulatory T cells. As noted here, treatment with CUE-401 resulted in significant induction and expansion of regulatory T cells.

The base level of natural Tregs is around 2% to 5% of the CD4-positive T cells upon treatment with CUE-401 up to 50% or greater of the CD4 positive T cells differentiated into the Treg phenotype. We have extensively characterized the Tregs induced and expanded by CUE-401.

The phenotype and genotype of these T cells are stable and robust and they demonstrate functional suppression in cell-based assays. In a collaboration with Dr. Richard DiPaolo's laboratory at the St. Louis University, we've also demonstrated in vivo conversion of Tregs and the functionality in murine models of autoimmunity.

An example is shown on the next slide, Slide 17. In this model of T cell-mediated autoimmune gastritis mice were treated with only two doses of CUE-401 at day 1 and day 14, and the disease assessments were performed post 60 days.

As shown here, the histological analysis of the stomach tissues showed extensive pathology and destruction in the mice treated with PBS, which is a controlled middle panel. In contrast, the mice treated with CUE-401 demonstrated protection from autoimmune destruction and their stomach tissue histology look more similar to the healthy controlled mice.

The graph on the right measures various metrics to generate a composite gastritis score. In this blinded assessment of histology sections, the Q401-treated mice exhibited significant reduction in the gastritis scores compared to the PBS-treated disease mice. The. next slide highlights the vast therapeutic opportunities with CUE-401.

These indications span from the well-known autoimmune diseases such as lupus, IBD, rheumatoid, arthritis, type 1 diabetes, et cetera. to opportunities in neuro inflammatory disorders such as multiple sclerosis, ALS, Alzheimer's, to pulmonary and metabolic diseases and sod and open transplantation NGVHD.

We are most excited about developing CUE-401 to address many of the indications noted here. The recently announced partnership with Ono Pharmaceuticals provides us with resource support as well as a series of defined milestone payments to support the further development of CUE-401 towards IND filing and clinical development.

Importantly, we have retained an option for 50% interest in the U.S. market, providing significant commercial potential to CUE if the drug is successfully developed and approved. With that, I'll now turn the call over to Kerri to give us a brief financial update.

Kerri?.

Thanks, Anish. Turning now to Slide 19. I'd like to provide a brief update on our financial results for the year ended December 31, 2022. The company reported collaboration revenue of approximately $0.15 million and $8.3 million for the three months ended December 31, 2022 and 2021, respectively.

The decrease was primarily due to the completion of the research phase of the LGC collaboration in the first quarter of 2022. Research and development expenses were $11.3 million and $11.5 million for the three months ended December 31, 2022 and 2021, respectively.

The decrease was due to the completion of enrollment in the Phase I monotherapy clinical trial of CUE-101 in recurrent or metastatic head and neck squamous cell carcinoma in the beginning of 2022. We General and administrative expenses were $3.7 million and $4.7 million for the three months ended December 31, 2022 and 2021, respectively.

The decrease was primarily due to lower stock-based compensation expense recorded during the first quarter of 2022 as compared to the same period in 2021. The company reported collaboration revenue of approximately $1.2 million and $14.9 million for the years ended December 31, 2022 and 2021, respectively.

The decrease was primarily due to the completion of the research phase of the LGC collaboration in the first quarter of 2022.

Research and development expenses for the year were $38.6 million and $41.3 million for December 31, 2022 and 2021, respectively, and the decrease was due to a decrease in costs related to clinical trial activity for the CUE-101 monotherapy and combination clinical trials and lower manufacturing costs related to the CUE-101 and CUE-102 clinical material.

General and administrative expenses were $16.2 million and $17.3 million for the years ended December 31, 2022 and 2021, respectively. The decrease in general and administrative expenses was due primarily to lower professional and consulting fees, stock-based compensation and rent in 2022.

As of December 31, 2020, the company had approximately $76.3 million in cash, cash equivalents and marketable securities as compared to $64.4 million as of December 31, 2021. Our current cash equivalents and marketable securities will fund operations into the second half of 2024.

I'll now turn the call back over to Dan, who will -- for his closing remarks.

Dan?.

Yes. Thanks, Kerri. I can go to the next slide. And look, in summary, we believe we are well positioned to achieve our stated objectives.

With CUE-101 exemplary of the IL-2-based CUE-100 series, demonstrating clear evidence of single-agent clinical activity and what appears to be at least a doubling of overall response in combination with KEYTRUDA and frontline patients. We believe we're beginning to observe what may prove to be a therapeutic breakthrough.

Importantly, CUE-101 has demonstrated clinical activity in combination with KEYTRUDA in patients having a low CPS score, that is in patients whose tumors appear to be immunologically inactive or less active, where a checkpoint inhibitor is thought to be less likely to provide benefit.

We believe our drug is mechanistically complementing checkpoint inhibition by activating and expanding targeted cancer-specific T cells in a well-tolerated manner, thereby broadening the patient reach and enhancing therapeutic outcome.

We're focused on the following core initiatives and milestones intended to further strengthen our competitive positioning. The emerging survival data in the CUE-101 monotherapy expansion cohort in the third line refractory metastatic HPV positive head and neck cancer patients.

is approaching a median overall survival of 12 months and beyond, which represents substantial benefit when compared to the historical median survival of eight months observed in second line with checkpoint inhibitors.

The strength of this data provides us with the opportunity of conducting a potential Registrational trial in patients that have progressed on prior chemotherapy and checkpoint inhibitor therapy.

CUE-101 plus pembrolizumab or KEYTRUDA combination in the expansion cohort is expected to complete enrollment of the full 20 patients midyear with a potential registrational trial being defined by the end of the year.

As reported, we continue to be highly encouraged by the data presented at SITC on the first 10 patients enrolled to date, follow-up analysis of these initial 10 patients as well as additional patients dosed and evaluated to date continue to hold or enhance what appears to be a doubling of the ORR compared to the checkpoint inhibition alone based on historical data as reported.

Our observations from the ongoing clinical trials appears to support the premise that CUE-101 and by implication, the entire CUE-100 series mechanistically complements checkpoint inhibition. And as such, we believe our platform and growing pipeline, expands patient reach and therapeutic benefit of checkpoints.

Turning to CUE-102, the monotherapy dose escalation trial is going quite well. CUE-102 target Wilms tumor 1. Just to remind you that WT1 expressing cancers represents a very broad opportunity. We believe that evidence of clinical activity would be a significant catalyst for further validation and value enhancement of our platform.

And we expect data from the dose-escalation trial to report in the second half of the year with significant potential market opportunities, as I stated, in WT1 positive cancer indications.

With that, we look forward to providing you with ongoing updates in the coming months, and we'd like to thank those listening in very much for your attention and interest in Cue Biopharma, and I'd like to turn the call back to the operator for questions.

Operator?.

[Operator Instructions] Our first question comes from the line of Ted Tenthoff with Piper Sandler. Please proceed..

Great. Thank you very much. Looking like it's picking up to be a really exciting year for you guys. I wanted to get a sense for what else we should be expecting from 101 in terms of data? And what else do you guys expect to learn in terms of helping define or design, sorry, the registrational trial? Thank you..

Sure. So thanks, Ted. Good to hear from you. I'll take that generically, and then I'll turn that over to Matteo and Ken. So right now, we're still in the dose -- the patient expansion phase of the combination. We are going to be filling that out, let's say, by midyear -- and as we've stated, that data continues to be followed and looks promising.

We're clearly looking at overall response rate, and we're very encouraged by what we're seeing. We're also looking at biomarker metrics such as the self-circulating HPV DNA as a proxy of response. Anish's group evaluates the PK/PD of these patients. So we're following those metrics accordingly.

And obviously, progression-free survival is being monitored as well as overall survival. All of these metrics are currently looking very supportive and promising. So that's what we intend to be gathering and reporting, say, second half of the year, and all of that will go into the -- our corresponding registration strategy.

Regarding strategy going forward, we have potential registration path for the monotherapy, principally based on median overall survival, but a lot of supporting metrics going into that. And we have the registration trial potential with the combination. What we're doing is just looking -- we feel fortunate that we have options there.

Just based on the current capital markets and limited resources, we need to be very prudent on what we prioritize and focus upon, and we're going to have discussions with the FDA and obviously, discussions with potential partners to determining which approach we're going to take the actual design of the trial we're working out in discussion with our participating investigators, et cetera.

I'm going to stop there, turn it over to Matteo and Ken if they want to add something in further more detail..

Thanks, Dan. No, I think you've covered it quite well.

I would just reemphasize that it's really the strength of the data as it's evolving and maturing that really provides options from a regulatory registrational point of view, for development, both as a monotherapy in laddered lines is really late line patients, so patients that have progressed on prior chemo and checkpoint inhibitor that's really an area that represents an unmet need where there's really no standard of care.

And so one could really, I think, envision considering a very efficient randomized trial, looking at the monotherapy versus an investigator's choice of regimens.

With regards to the combination, you'd ask about the data sets really by the end of the year, we should have rather mature data on the response rates for the 20 patients to be enrolled in Part D.

And really, the efficacy that we're observing to date, if that's maintained and strengthened positions that to enable a trial really that could have a proximal endpoint of PFS or objective response rate in the context of a confirmatory enrolled patient trial that could potentially support an earlier approval. So just a couple of additional thoughts.

It's really the strength of the data in both lines as it evolves, I think, that gives us many options to consider..

Excellent. That's very helpful. Looking forward [indiscernible]..

Okay. Thanks Ted..

Our next question comes from the line of Ren Benjamin with JMP Securities. Please proceed..

Hi, good afternoon, guys. Thanks for taking the questions. And congratulations on the progress. I guess I'd like to just kind of start off, start off.

You mentioned patient A, patient B and patient C I'd love to just kind of get your thoughts maybe from Ken or Sara if she's on as to one reasons for potential relapse, is there any work or anything that you might be able to gather from interacting with the patient or any of the biomarker studies that might give you some clues as to that? And then the other kind of related to it, more on the combo side is you have these objective responses like the PRs, but have you observed, I think you did in the monotherapy portion of the study, a deepening of response where SDs are becoming PRs and what is driving those kinds of responses? And then I have a follow-up..

So this is Ken. Sara had a drop off a few minutes ago to -- go to see a patient. But basically, patients fail primary therapy because tumor cells are left behind. And currently, an activated immune system is not in place to wipe out any remaining microscopic nests of cells that we just don't see.

So with radiation or surgery, we just have left a cell behind and our own immune systems don't clean them up. I mean -- so we're very interested, for example, in the neoadjuvant study we have going on to see if we can activate T cells by using CUE-101 to try and get those last cells cleaned up.

And that's what we're seeing over and over in all of cancer, including head and neck cancer, that it's these unseeable few cancer cells that are left behind that we have to figure out how to get cleaned up by activating the immune system. So I'll stop there and see if that answered your question or if you need further -- need more..

Yes. So you mentioned the neoadjuvant study and as I was kind of quickly stepping out the milestones for this year, I might have missed when we might see something regarding the neoadjuvant study.

Can you just give us an update as to how that's progressing and when we might see some initial results from that study?.

I'll give that one to Matteo since..

The neoadjuvant trial is going well. The first cohort of patients in schema 1 have been fully enrolled. And the preliminary data looks very, very intriguing, whereby we've seen evidence of expansion of V7 reactive T cells and increases in NK cells.

So -- the study now is currently recruiting and enrolling Schedule B, which is two doses prior to surgery or definitive treatment. And we'd anticipate completing enrollment into that cohort by the end of the year..

Got it. Okay. Thank you. And then just as we think about the registrational potential registrational studies, I guess then, if we take out the potential for a partner. Let's just say that's a discussion that winds up taking too long.

Can you just maybe take us through the steps that would, I guess, help you decide like which trial to go ahead and start like I would think that the refractory monotherapy study is the way to go.

But I don't know what are the other factors that you might be thinking about as you decide to commit to one or the other?.

Yes. And so it's a really important question, Ren. And it's one that we obviously are looking at very seriously and dynamically in the various factors we have to consider. So for instance, you just mentioned monotherapy, maybe the more attractive ones since it is monotherapy direct path forward.

It's primary readout is the -- is basically median overall survival. We have to follow patients. Also bear in mind, it's a smaller market. And so part of countering that is in the front line, which is further upstream broader market of patients, we're seeing these very promising results.

So by essence of the promise of those results, we would be potentially shrinking that downstream market even further. So -- and what we'd be measuring there is you probably would be overall response rate, clearly, we'd be following median overall survival, but it's a broader market.

And we're also looking at moving even more upstream there with the neoadjuvant adjuvant setting, for instance. So these are kind of the various factors we have to consider.

And it also has to do with the capital access that we have, whether it is through a partnership, if we're doing it ourselves, we have to think about the size of the study and the duration of that study. So all of those variables are being considered.

I think the important take home for us right now at this point in time is we have the prospect of more than one potential registration path to choose from..

Fair enough. Thanks very much for taking the questions..

Okay. Thank you, Ren..

Our next question call comes from the line of Mark Breidenbach with Oppenheimer. Please proceed..

Hi, good afternoon. Thanks for taking our questions. Just some timing questions for me to make sure I heard you guys correctly. We should be expecting the next data both from the CUE-101 combination study in the second half of this year as well as the initial data from CUE-102.

So first of all, is that correct? And second, what should we expect in the CUE-102 data? Is it just be safety and PK data initially? Or should we kind of expect a more complete analysis of the dose escalation cohorts from that? And I have a follow-up..

Sure. All right. Thanks, Mark. Appreciate it. So the first question, just to clarify, when we said the second half of the year, that's the sort of completed analysis or the analysis of the completed 20 patient expansion. The next update we'll be providing is at an upcoming oncology conference. So that could be midyear.

We're not going to wait until second half of the year to release an update. So what we're referring to the second half is that's all 20 patients completed surveyed, et cetera, a more deeper analysis. So I hope that's helpful. We're looking at an update probably midyear at a cancer conference.

And then regarding the metrics on 102, I think the way you couched the question that's actually the answer is we'll be doing the dose escalation, completing that by midyear, and we'll be providing the corresponding metrics that we've been measuring along the way, which, in fact, has to do with PK/PD, a possibility, obviously, of some clinical activity as well.

And that's going to be midyear, second half of the year. Matteo, I don't know if you want to add anything to that? If not, that's fine..

No, that's fine. Nothing to add..

Okay. That's super helpful. Thanks for that clarification. And then just maybe one for Anish on CUE-401.

I'm just wondering if you have any plans to present head-to-head preclinical comparisons versus some of the other IL-2 muteins that are out there? Is that something that's on the agenda for 2023?.

Yes, Mark, we've actually, in previous meetings, and there's an upcoming Treg meeting in May, where we're talking. But in a meeting in Paris last year, we presented on this where we compare this to CD25-biL-2-mutein where we show clear induction by CUE-401 where the IL-2 mutein as expected, did not convert. And that's not surprising.

It is the anticipated immunological outcome. We're continuing to build on that data and in vivo models as well, and we'll be discussing that in the future. But so far, the biology strongly supports the induction and generation of new populations of Tregs which 401 can do but obviously a CD25 biased IL mutein cannot..

Okay. Thanks for taking the question..

Thanks Mark..

Thank you. [Operator Instructions] And our next question comes from the line of Stephen Willey with Stifel. Please proceed..

Yes, good afternoon. Thanks for taking the questions. Congrats on progress. So on CUE-102, I know you're talking about monotherapy dose escalation initiating dose expansion monotherapy.

But are there plans to initiate dose escalation with CUE-102 in combination with the checkpoint inhibitor? And I guess, is that something that you would expect to start in parallel with monotherapy dose escalation?.

Very good question. And the answer is yes. I mean, obviously, it's very similar to 101. We expect same general pattern. We are -- just to remind everyone, our first trial is with pembrolizumab, but we expect that our drugs in platform will work with any checkpoint.

So we're looking at various options and alternatives presently, but that is our intent to also survey in combination it's first to show the monotherapy tolerability profile, which we expect to, in essence, mirror what we've seen with 101. But obviously, having that data will be important. And then as you have stated, that's the natural next step..

Okay.

And would you be prespecifying tumors to be WT1 positive with the combination as well? And then I guess, does the monotherapy dose expansion then maybe inform select tumor types for expansion with combo?.

So the answer is yes to both of those questions. Yes, we will be stratifying patients based on WT1 expression and then also in terms of the type of cancers. And the 101 -- I'm sorry, the 102 monotherapy will certainly guide our thinking of tumors that are more responsive. So that's absolutely spot on both questions..

Okay. And I guess, there appears to be a bit more discussion just around the pursuit of partnering opportunities.

And I guess just philosophically, curious if you think that the more proximal opportunities for you are also autoimmune focus, maybe with the CUE-300 series? Or do you think that there's an opportunity here with either the two CUE-100 programs we know about, maybe some more that we don't know about that could be kind of put out to bid?.

Yes. So Steve, it's a really important question, complicated question because there are a lot of different perspectives on that and variables we have to consider. I think what we're trying to emphasize is this partnership we just announced with Ono. It's not a -- it's sort of classic license for some money. We're actively involved.

They're a collaborator. They're supporting the preclinical development work. We have an option to codevelop. They pay milestones along the way. Those milestone payments go a long way to subsidizing our portion if we decide to co-develop and that allows us to basically retain a significant upside.

And what we're trying to basically state here is we have no intention of partnering assets where we're doing preclinical work and then licensing the upside so that we're just monetizing assets. We want to be involved, but the key is to have leverage through the power of the data that we're generating.

And we think with the 101 and hopefully 102 following behind data sets that we're developing. This basically validates the whole 100 Series. And what we'd like to be in a position of leverage in terms of structuring partnerships that allow us to subsidize some of the costs, i.e., capitalization risk but retain significant upside.

We also would benefit from the depth of clinical development capabilities from various partners in the checkpoint space. So we're not adverse to partnering 101 and 102, but we're certainly not going to hand over the upside of the asset to somebody and just do preclinical work. So we intend to be involved.

So we have retained interest and involvement and commercialization rates hopefully in co-development. But also what you stated, the 300 series is also a natural point for partnering as well. We have a very attractive data set there..

All right. It's very helpful. Thanks for taking the questions..

Yes, thank you..

Thank you. There are no further questions at this time. I'd like to turn the call back to Dan Passeri for closing remarks..

Yes. Thank you. Again, I just want to thank everyone for your time and attention during these trying times in the market and really appreciate your time, and we look forward to providing you with ongoing updates particularly midyear, right. Thank you very much. Bye-bye..

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation, and have a great day..